Cobalt-Catalyzed Cross-Couplings between Alkenyl Acetates and Aryl or Alkenyl Zinc Pivalates

Article abstract of DOI:10.1002/anie.201805486

CoBr₂ (5 mol %) in the presence of 2,2′-bipyridyl (5 mol %) enables electrophilic alkenylations between easily accessible alkenyl acetates or tosylates and various functionalized aryl zinc pivalates at ambient temperature. This cobalt-catalyzed

Full text of DOI:10.1002/anie.201805486

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Title: Cobalt-Catalyzed Cross-Couplings between Alkenyl Acetates and
Aryl- or Alkenyl-Zinc Pivalates
Authors: Jie Li and Paul Knochel
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10.1002/anie.201805486
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Cobalt-Catalyzed Cross-Couplings between Alkenyl Acetates and
Aryl- or Alkenyl-Zinc Pivalates
Jie Li, and Paul Knochel*
Abstract: CoBr2 (5 mol %) in the presence of 2,2'-bipyridyl (5 mol %) Ackermann[15] and Yoshikai[16]
, displayed a positive effect
enables electrophilic alkenylations between easily accessible alkenyl
acetates, tosylates and various functionalized arylzinc pivalates at
ambient temperature. Moreover, this cobalt-catalysis was further
applicable to alkenylzinc pivalates to provide substituted 1,3-dienes.
leading to 3a in 27% (entry 5). However, chelating ligands such
as bis-pyridines, increased the yield of 3a to 31‒59% (entries
6‒8). Switching CoCl2 to Co(acac)2 or CoBr2 lead to a further
yield increase to 87% (entries 9‒10). Performing this reaction at
23 °C instead of 50 °C using 2,2'-bipyridyl (bpy) led to 3a in the
same yield (16 h reaction time, entry 11). The easily prepared
and bench-stable CoBr2(bpy) catalyst[17] furnished the desired
product 3a as well, albeit in a slightly reduced yield (entry 12).
Other organometallics, such as PhMgCl·LiCl, PhAlCl2·LiCl, and
Ph(Et)AlCl·LiCl did not furnish the desired product.[18]
Cobalt-catalyzed cross-couplings[1] are industrially- and eco-
friendly carbon-carbon forming reactions, because cobalt salts
display low toxicity[2] and are requiring simple ligands.[3,4] Aryl-
and heteroaryl-magnesium[5] or zinc reagents are especially
attractive, because these organometallics are compatible with a
variety of functional groups. Of special interest are arylzinc
pivalates which show an enhanced air and moisture stability and
can be stored as solids under argon for several months.[6] These
zinc organometallics[7] undergo cobalt-catalyzed cross-couplings
with various unsaturated halides.[3] Unsaturated pivalates and
acetates have been used as electrophilic partners for transition-
metal-catalyzed cross-couplings with organometallic reagents
derived from B, Si, Zn, Al, and Mg using Ni,[8] Rh[9] or Fe[10] as
catalysts. Despite these major advances, the use of expensive
or toxic Rh, Ni catalysts still remain a drawback. Thereafter,
cobalt-catalyzed cross couplings of aryl halides with vinyl
acetates using an electrochemical setup[11] or Mn as reductant[12]
were developed by Gosmini and coworkers, albeit with a limited
substrate scope of vinyl acetates. Recently, Ackermann
described also a direct C‒H alkenylation of indoles with
unactivated alkenyl acetates using a cobalt-NHC catalysis.[13]
Unsaturated acetates[10a,14] have attracted considerable attention
in organic synthesis due to the halide-free nature of this leaving
group. Herein, we report a novel cobalt-catalyzed cross-coupling
between aryl- and alkenyl-zinc pivalates and various
functionalized alkenyl acetates under mild reaction conditions at
ambient temperature.
Table 1. Optimization for cobalt-catalyzed arylation of alkenyl acetate 2a.[a]
Entry
[Co]
Ligand (5 mol %)
yield (%)[b]
1
2
--
CuI
bpy
0
bpy
0
3
Fe(acac)2
CoCl2
(20 mol %) TMEDA
0
4
--
IPrHCl
4,4'-dmbpy
4,4'-dtbpy
bpy
18
27
31
51
59
83
87
5
CoCl2
6
CoCl2
7
CoCl2
8
CoCl2
9
Co(acac)2
CoBr2
CoBr2
CoBr2(bpy)
bpy
10
11
12
bpy
First, we have optimized the reaction conditions for the cobalt-
catalyzed olefination of PhZnOPiv (1a) with ethyl 2-
acetoxycyclohexenylcarboxylate (2a). No reaction was observed
in the absence of transition metal salts, or in the presence of a
copper salt (CuI) or Fe(acac)2 (Table 1, entries 1‒3). However,
in the presence of CoCl2 (5 mol %) a cross-coupling was
observed and the arylated product (3a) was obtained in 18%
isolated yield (entry 4). Among various ligands, N-heterocyclic
carbene ligands, such as IPrHCl, IMesHCl,[10b] which were
broadly used in the cobalt-catalyzed C‒H functionalizations by
c
]
bpy
86[
--
70[c]
[a] Reaction conditions: 2a (0.75 mmol), 3a (0.50 mmol), [Co] (5.0 mol %),
ligand (5.0 mol %), THF (2.0 mL), 50 °C, N2, 16 h. [b] Isolated yields. [c] 23 °C.
bpy = 2,2'-bipyridine; TMEDA = N,N,N',N'-tetramethylethylenediamine; IPrHCl
= 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride; 4,4'-dtbpy = 4,4'-di-tert-
butyl-2,2'-dipyridyl; 4,4'-dmbpy
acetylacetonate.
=
4,4'-di-methyl-2,2'-dipyridyl; acac
=
With these optimized conditions in hand, we have investigated
the scope of the cross-coupling of alkenyl acetates with
organozinc pivalates (Table 2). All arylzinc pivalates were
prepared from the corresponding aryl bromides by Mg insertion
in the presence of LiCl[19] or by Br/Mg-exchanges using
iPrMgCl·LiCl,[7b] followed by transmetallation with Zn(OPiv)2
(Table 2). ArZnCl·Mg(OPiv)2·LiCl was abbreviated as ArZnOPiv
for the sake of clarity.[6] Notably, various arylzinc pivalates
(1a‒1f) underwent the alkenylation with 2a to afford the desired
products (3a‒3f) in 75‒88% yield (Table 2, 1‒6). There was no
significant influence of the ring size of acetates 2. Indeed, five-
[*]
Dr. J. Li, Prof. Dr. P. Knochel
Department of Chemistry
Ludwig-Maximilians-Universitӓt München
Butenandtstr. 5-13, Haus F, 81377 Munich (Germany)
E-mail: paul.knochel@cup.uni-muenchen.de
Dr. J. Li
School of Pharmaceutical Science
Jiangnan University
Lihu Road 1800, 214122 Wuxi, Jiangsu (China)
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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or seven-membered acetates including the indenyl acetate (2d)
were arylated with phenylzinc pivalate (1a) leading to the
phenylated products (3g‒3j) in excellent yields (entries 7‒10).
Moreover, this cross-coupling was extended to 4-acetoxy-6-
methyl-2-pyrone (2e) and 4-acetoxy-2-chromen-one (2f), albeit
the corresponding arylated products 3k‒3l were obtained in
48‒52% yield (entries 11‒12).
10
11
1g
1a
2d
2e
3j: 98%
Table 2. Substrate scope of the cobalt-catalyzed arylation of enol acetates of
type 2 leading to arylated products of type 3.
3k: 48%[b]
12
1a
2f
3l: 52%[b]
[a] Yields of isolated analytically pure products. [b] 1a (3.0 equiv), CoBr2 (10
mol %), bpy (10 mol %), 50 °C, N2, 16 h.
Also, we have found that alkenyl tosylate (4a) and alkenyl
pivalate (5a) readily underwent in this electrophilic alkenylation
(Table 3, entry 1). Moreover, this cobalt-catalyzed cross-
coupling reaction using tosylates 4b‒4e was found to be
stereoconvergent. Thus, the reaction of E- or Z-tosylates 4b and
4c gave the same (E)-product 3m in 84‒88% (entries 2 and 3).
Similarly, the cross-coupling with E- or Z-tosylates 4d and 4e
gave the same (E)-unsaturated ester 3n in 76‒83% yield
(entries 4 and 5).[20] However, electron-withdrawing arylzinc
pivalate 1h gave the corresponding product 3 in 94% yield with a
Z/E ratio 1:1.
Arylzinc pivalate of
Alkenyl acetate
Entry
Product of type 3[a]
type 1
of type 2
1
2
1a
1b
2a
2a
3a: 86%
3b: 75%
Table 3. Cobalt-catalyzed cross-coupling reactions between arylzinc pivalates
1 and enol tosylates 2.
3
4
1c
1d
2a
2a
3c: 88%
3d: 77%
Arylzinc pivalate of
Alkenyl tosylate
Entry
Product of type 3[a]
type 1
of type 4
1a
1a
4a (R = OTs)
5a (R = OPiv)
3a: 87%
3a: 84%
1
5
1e
2a
3e: 82%
2
3
4
1a
1a
1a
4b
4c
4d
3m: 88%
3m: 84%
3n: 83%
6
7
1f
2a
2b
3f: 88%
3g: 91%
1a
8
9
1a
1a
2c
2d
3h: 92%
3i: 91%
5
1a
4e
3n: 76%
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6
7
1d
1h
4a
4a
3o: 82%
7
8
1i
6g
6h
7g: 60%
7h: 92%
3p/3p': 94%
(1:1)
1g
[a] Yields of isolated analytically pure products.
[a] Yields of isolated analytically pure products.
Additionally, 1-styryl acetates of type 6 bearing various
functional groups were also further examined under our
standard reaction conditions (Table 4). Thus, unsubstituted or
methoxy, nitrile, ester para-substituted styryl acetates 6a‒6d
were well tolerated by the cobalt catalyst, delivering the
corresponding products 7a‒7d in 61‒96% yield. The
unsaturated acetate 6e bearing an ortho-fluoro, as well as 6f
were smoothly converted to the arylated alkenes (7e‒7f) in
65‒81% yield. Remarkably, the styryl acetate 6g (E/Z 2:1) led to
a stereoselective reaction with arylzinc pivalate (1i) under our
1,3-Dienes are very important structural motif found in natural
products with biological activity.[21] In this context, we have found
such 1,3-dienes are obtained by the cobalt-catalyzed alkenlation
using alkenylzinc pivalates (Scheme 1). Both isopropenylzinc
pivalates and α-arylvinylzinc pivalates 8 as well as various
alkenyl acetates (2a‒2d) provide substituted dienes 9a‒9f in
48‒69% yield.
standard
reaction
conditions,
thereby
yielding
the
thermodynamically most stable E-alkene 7g (E/Z 99:1, entry 7)
as the sole product with 60% yield.[20] As expected, the arylzinc
pivalate (1g) also reacts with 2-propenyl acetate 6h giving
product 7h in 92% yield (entry 8).
Table 4. Substrate scope of alkenyl acetates 6 leading to arylated products of
type 7.
Scheme 1. Cobalt-catalyzed cross-coupling of alkenylzinc pivalates 8 with
alkenyl acetates 2 leading to dienic esters of type 9.
Arylzinc
pivalate of
type 1
Alkenyl acetate
Entry
Product of type 7[a]
of type 6
1
2
3
1g
1c
1c
6a
6b
6c
7a: 94%
7b: 61%
7c: 79%
Scheme 2. Synthesis of estrone derivatives 12a‒12b through cobalt-catalyzed
C‒C bond forming reactions.
4
1g
6d
7d: 96%
Finally, the synthetic utility of this cobalt-catalyzed arylation
protocol for the synthesis of pharmacologically relevant
compounds was demonstrated by a concise derivatization of
estrone 10 (Scheme 2). Alkenyl acetate 11 was obtained in 72%
5
6
1i
6e
6f
7e: 65%
7f: 81%
yield
through
α-oxycarbonylation[22]
and
esterification
reactions.[23] Subsequently, cobalt-catalyzed cross-coupling of
1d
11 with arylzinc pivalates (1a and 1d) furnish the arylated
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estrones (12a‒12b) in 90‒92% yield. Preliminary mechanistic
studies demonstrated that CoI-complexes are also active
complexes.[24]
In summary, we have reported a practical cobalt-catalyzed
electrophilic alkenylation between functionalized aryl- and
alkenyl-zinc pivalates and various alkenyl acetates under mild
reaction conditions. This catalytic system displayed excellent
functional group tolerance, as well as high stereoselectivity.
Moreover, a derivatization of estrone demonstrated the synthetic
versatility of our method.
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Acknowledgements
We thank the Deutsche Forschungsgemeinschaft (DFG) and the
National Natural Science Foundation of China (Grant No.
21602083) for financial support. We also thank the Fundamental
Research Funds for the Central Universities (JUSRP51703A).
Conflict of interest
The authors declare no conflict of interest.
Keywords: cobalt catalysis• alkenylation • alkenyl acetates •
organozinc reagents • dienes
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J. Li, P. Knochel*
Page No. – Page No.
Cobalt-Catalyzed Cross-Couplings
between Alkenyl Acetates and Aryl-
or Alkenyl-Zinc Pivalates
Cobalt-catalyzed alkenylations. A range of functionalized aryl- and alkenyl-zinc
pivalates underwent cobalt-catalyzed alkenylations with alkenyl acetates in good
yields under a remarkably mild reaction conditions at 23 ̊C. This efficient catalytic
system tolerated various functional groups and proceeded with excellent
stereoselectivity (Z:E < 1:99).
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